J.-F. Bosset

Nomograms for Predicting Local Recurrence, Distant Metastases, and Overall Survival for Patients With Locally Advanced Rectal Cancer on the Basis of European Randomized Clinical Trials

PURPOSE The purpose of this study was to develop accurate models and nomograms to predict local recurrence, distant metastases, and survival for patients with locally advanced rectal cancer treated with long-course chemoradiotherapy (CRT) followed by surgery and to allow for a selection of patients who may benefit most from postoperative adjuvant chemotherapy and close follow-up. PATIENTS AND METHODS All data (N = 2,795) from five major European clinical trials for rectal cancer were pooled and used to perform an extensive survival analysis and to develop multivariate nomograms based on Cox regression. Data from one trial was used as an external validation set. The variables used in the analysis were sex, age, clinical tumor stage stage, tumor location, radiotherapy dose, concurrent and adjuvant chemotherapy, surgery procedure, and pTNM stage. Model performance was evaluated by the concordance index (c-index). Risk group stratification was proposed for the nomograms. RESULTS The nomograms are able to predict events with a c-index for external validation of local recurrence (LR; 0.68), distant metastases (DM; 0.73), and overall survival (OS; 0.70). Pathologic staging is essential for accurate prediction of long-term outcome. Both preoperative CRT and adjuvant chemotherapy have an added value when predicting LR, DM, and OS rates. The stratification in risk groups allows significant distinction between Kaplan-Meier curves for outcome. CONCLUSION The easy-to-use nomograms can predict LR, DM, and OS over a 5-year period after surgery. They may be used as decision support tools in future trials by using the three defined risk groups to select patients for postoperative chemotherapy and close follow-up (http://www.predictcancer.org).

EORTC-ROG expert opinion: Radiotherapy volume and treatment guidelines for neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction and the stomach

PURPOSE The Gastro-Intestinal Working Party of the EORTC Radiation Oncology Group (GIWP-ROG) developed guidelines for target volume definition in neoadjuvant radiation of adenocarcinomas of the gastroesophageal junction (GEJ) and the stomach. METHODS AND MATERIALS Guidelines about the definition of the clinical target volume (CTV) are based on a systematic literature review of the location and frequency of local recurrences and lymph node involvement in adenocarcinomas of the GEJ and the stomach. Therefore, MEDLINE was searched up to August 2008. Guidelines concerning prescription, planning and treatment delivery are based on a consensus between the members of the GIWP-ROG. RESULTS In order to support a curative resection of GEJ and gastric cancer, an individualized preoperative treatment volume based on tumour location has to include the primary tumour and the draining regional lymph nodes area. Therefore we recommend to use the 2nd English Edition of the Japanese Classification of Gastric Carcinoma of the Japanese Gastric Cancer Association which developed the concept of assigning tumours of the GEJ and the stomach to anatomically defined sub-sites corresponding respectively to a distinct lymphatic spread pattern. CONCLUSION The GIWP-ROG defined guidelines for preoperative irradiation of adenocarcinomas of the GEJ and the stomach to reduce variability in the framework of future clinical trials.

What is the clinical benefit of preoperative chemoradiotherapy with 5FU/leucovorin for T3-4 rectal cancer in a pooled analysis of EORTC 22921 and FFCD 9203 trials: Surrogacy in question?

BACKGROUND Two phase III trials of neoadjuvant treatment in T3-4 rectal cancer established that adding chemotherapy (CRT) to radiotherapy (RT) improves pathological complete response (pCR) and local control (LC). We combined trials to assess the clinical benefit of CRT on overall (OS) and progression free survival (PFS) and to explore the surrogacy of pCR and LC. PATIENTS AND METHODS Individual patient data from European Organisation for Research and Treatment of Cancer (EORTC) 22921 (1011 patients) and FFCD 9203 (756 patients) were pooled. Meta-analysis methodology was used to compare neoadjuvant CRT to RT for OS, PFS LC and distant progression (DP). Weighted linear regression was used to estimate trial-level association (surrogacy R(2)) between treatment effects on candidate surrogate (pCR, LC, DP) and OS. RESULTS The median follow-up was 5.6 years. Compared to RT (881 pts), CRT (886 pts) did not prolong OS, DP or PFS. The 5-y OS-rate was 66.3% with CRT versus 65.9% in RT (hazard ratios (HR) = 1.04 {0.88-1.21}). CRT significantly improved LC (HR = 0.54, 95%confidence interval (CI): 0.41-0.72). PFS was validated as surrogate for OS with R(2) = 0.88. Neoadjuvant treatment effects on LC (R(2) = 0.17) or DP (R(2) = 0.31) did not predict effects on OS. CONCLUSION Preoperative CRT does not prolong OS or PFS. pCR or LC do not qualify as surrogate for PFS or OS while PFS is surrogate. Phase III trials should use OS or PFS as primary endpoint.

Role of Radiotherapy With Surgery for T3 and Resectable T4 Rectal Cancer: Evidence From Randomized Trials

PurposeThe main treatment for resectable rectal cancer T2–T4 N0–N2 M0 is surgery. The benefit of preoperative or postoperative radiation therapy can be analyzed in terms of improvement of local control, sphincter preservation, and survival weighted against increased toxicity.MethodsOnly randomized trials can provide strong evidence of a positive cost-benefit ratio of such combined approach. The most recent trials were reviewed.ResultsThree randomized trials, including the latest German CAO-ARO trial, have demonstrated the superiority of preoperative radiotherapy with or without chemotherapy (vs. postoperative) in terms of local control and toxicity. The Ducth TME trial showed that even with modern standard surgery, preoperative radiotherapy improved local control. Preoperative irradiation using a high dose in a small volume and a long interval before surgery may improve sphincter preservation (Lyon trials). Concurrent chemoradiation (FFCD 9203, EORTC 22921, did not significantly improve sphincter preservation or survival but significantly reduced the local recurrence rate.ConclusionsIn 2005 examination of randomized trials provides evidence for the benefit of preoperative chemoradiation in improving local control and probably sphincter preservation in rectal cancer. Randomized trials should be designed to further demonstrate improved sphincter preservation and to increase survival using adjuvant medical treatments.

Feasibility of chemoradiotherapy for oesophageal cancer in elderly patients aged >or=75 years: a prospective, single-arm phase II study.

AbstractBackground: The number of elderly patients with oesophageal cancer is expected to increase with the aging of the population and the rapidly increasing incidence of adenocarcinoma. Surgical resection is standard treatment for patients with localized disease considered fit for operation. However, elderly patients with oesophageal cancer are rarely referred for surgery. Objective: The aim of this prospective, single-arm, phase II study was to evaluate the feasibility and efficacy (tumour response) of chemoradiotherapy in the treatment of elderly patients with localized oesophageal cancer. Secondary endpoints were progression-free survival (PFS) and quality of life (QOL). Methods: The main study inclusion criteria were: patients aged ≥75 years; oesophageal cancer disease stage II–III; Charlson co-morbidity index score ≤4; Eastern Cooperative Oncology Group (ECOG) performance status 0–2; and weight loss <15%. The radiotherapy regimen consisted of 50 Gy over 5 weeks. Cisplatin 75mg/m2 was given on days 1 and 21 of radiotherapy. Complete response was defined as disappearance of the tumour at endoscopy and/or at oesophagography and CT scan. Written informed consent was obtained from all patients. A three-step Fleming design was used to calculate the sample size. Results: Twenty-two patients were included in the study between March 2000 and June 2004; this sample size was sufficient to allow conclusions to be drawn from the study. The mean age of the patients was 79.4 years (range 75–89 years), 18 were male (81.8%), 15 had squamous cell carcinoma (68%) and 11 had stage IIA disease (50%). The mean Charlson co-morbidity index score was 1. All patients were compliant with the planned treatment, including doses and timing. During treatment, ECOG performance status remained stable during the first 3 weeks and worsened slightly over the last 2 weeks. Dysphagia remained stable. Five patients (22%) had transient grade 2 vomiting after the second cisplatin injection. No patient experienced nephrotoxic adverse effects and there were no toxicity-related deaths. Six weeks after treatment, 14 patients were in complete response (63.6%) and 8 patients (36.4%) had no treatment effect. The overall survival was 81.6% at 6 months and 62.4% at 1 year. The PFS at 1 year was 50%. Four patients (18.2%) were alive without disease from 2.6 to 5.5 years after treatment. In 14 evaluable patients, QOL 6 weeks after treatment was slightly altered by treatment. Conclusions: The results of this prospective phase II study support the feasibility of chemoradiotherapy for oesophageal cancer in carefully selected elderly patients, with the potential for a curative effect.BACKGROUND The number of elderly patients with oesophageal cancer is expected to increase with the aging of the population and the rapidly increasing incidence of adenocarcinoma. Surgical resection is standard treatment for patients with localized disease considered fit for operation. However, elderly patients with oesophageal cancer are rarely referred for surgery. The aim of this prospective, single-arm, phase II study was to evaluate the feasibility and efficacy (tumour response) of chemoradiotherapy in the treatment of elderly patients with localized oesophageal cancer. Secondary endpoints were progression-free survival (PFS) and quality of life (QOL). METHODS The main study inclusion criteria were: patients aged >or=75 years; oesophageal cancer disease stage II-III; Charlson co-morbidity index score <or=4; Eastern Cooperative Oncology Group (ECOG) performance status 0-2; and weight loss <15%. The radiotherapy regimen consisted of 50 Gy over 5 weeks. Cisplatin 75 mg/m2 was given on days 1 and 21 of radiotherapy. Complete response was defined as disappearance of the tumour at endoscopy and/or at oesophagography and CT scan. Written informed consent was obtained from all patients. A three-step Fleming design was used to calculate the sample size. RESULTS Twenty-two patients were included in the study between March 2000 and June 2004; this sample size was sufficient to allow conclusions to be drawn from the study. The mean age of the patients was 79.4 years (range 75-89 years), 18 were male (81.8%), 15 had squamous cell carcinoma (68%) and 11 had stage IIA disease (50%). The mean Charlson co-morbidity index score was 1. All patients were compliant with the planned treatment, including doses and timing. During treatment, ECOG performance status remained stable during the first 3 weeks and worsened slightly over the last 2 weeks. Dysphagia remained stable. Five patients (22%) had transient grade 2 vomiting after the second cisplatin injection. No patient experienced nephrotoxic adverse effects and there were no toxicity-related deaths. Six weeks after treatment, 14 patients were in complete response (63.6%) and 8 patients (36.4%) had no treatment effect. The overall survival was 81.6% at 6 months and 62.4% at 1 year. The PFS at 1 year was 50%. Four patients (18.2%) were alive without disease from 2.6 to 5.5 years after treatment. In 14 evaluable patients, QOL 6 weeks after treatment was slightly altered by treatment. CONCLUSIONS The results of this prospective phase II study support the feasibility of chemoradiotherapy for oesophageal cancer in carefully selected elderly patients, with the potential for a curative effect.

Pattern of occult nodal relapse diagnosed with 18F-fluoro-choline PET/CT in prostate cancer patients with biochemical failure after prostate-only radiotherapy

INTRODUCTION The purpose of this study was to describe the pattern of nodal relapse with (18)F-fluoro-choline (FCH) Positron Emission Tomography/Computerized Tomography (PET/CT) in prostate cancer patients after radiotherapy. MATERIALS AND METHODS Eighty-three patients had a FCH PET/CT at time of biochemical failure. Of 65 patients with positive findings, 33 had positive nodes. This analysis included 31 patients who had undergone prior prostate-only radiotherapy with or without a prior radical prostatectomy. Each FCH positive node was assigned to a lymph node station with respect to the CTV defined by the RTOG guidelines (CTVRTOG). 3D mapping was performed after each node was manually placed in a reference planning CT scan after automatic co-registration of the two scans based on bone anatomy. Eighteen patients (58%) underwent focal salvage FCH PET-guided stereotactic radiotherapy with no hormones. RESULTS Fourteen patients (45.2%) had a relapse outside the CTVRTOG. Of the 17 patients with a positive node inside the CTVRTOG, 15 had a single node (88.2%) while seven patients out of the 13 evaluable patients (53.9%) who had a relapse outside the CTVRTOG had ⩾2 positive nodes on FCH PET/CT (OR=8.75, [95% CI: 1.38-54.80], p=0.020). Relapses that occurred outside the CTVRTOG involved the proximal common iliac (19.3%) and lower periaortic nodes (19.3%) up to L2-L3. CONCLUSION 3D mapping of nodal relapses evaluated with FCH PET/CT suggests that with IMRT the upper field limit of pelvic radiotherapy could be extended to L2-L3 safely to cover 95% of nodal stations at risk of an occult relapse.

Selection of appropriate end-points (pCR vs 2yDFS) for tailoring treatments with prediction models in locally advanced rectal cancer

PURPOSE Personalized treatments based on predictions for patient outcome require early characterization of a rectal cancer patients sensitivity to treatment. This study has two aims: (1) identify the main patterns of recurrence and response to the treatments (2) evaluate pathologic complete response (pCR) and two-year disease-free survival (2yDFS) for overall survival (OS) and their potential to be relevant intermediate endpoints to predict. METHODS Pooled and treatment subgroup analyses were performed on five large European rectal cancer trials (2795 patients), who all received long-course radiotherapy with or without concomitant and/or adjuvant chemotherapy. The ratio of distant metastasis (DM) and local recurrence (LR) rates was used to identify patient characteristics that increase the risk of recurrences. FINDINGS The DM/LR ratio decreased to a plateau in the first 2 years, revealing it to be a critical follow-up period. According to the patterns of recurrences, three patient groups were identified: 5-15% had pCR and were disease free after 2 years (excellent prognosis), 65-75% had no pCR but were disease free (good prognosis) and 15-30% had neither pCR nor 2yDFS (poor prognosis). INTERPRETATION Compared with pCR, 2yDFS is a stronger predictor of OS. To adapt treatment most efficiently, accurate prediction models should be developed for pCR to select patients for organ preservation and for 2yDFS to select patients for more intensified treatment strategies.

Cancer du rectum : volumes cibles de la radiothérapie préopératoire

Resume La radiotherapie preoperatoire est le traitement standard des adenocarcinomes du rectum, localement evolues, mais qui restent resecables. L’augmentation du taux de controle local obtenue par l’exerese totale du mesorectum indique que le mesorectum est l’espace anatomique principal de diffusion des cellules tumorales. Il peut donc etre assimile au volume cible anatomo-clinique (CTV) de base dans l’elaboration de la radiotherapie conformationnelle preoperatoire. A partir des donnees anatomiques et de l’apport de l’imagerie, nous proposons la determination de plusieurs volumes cibles anatomo-cliniques en fonction de differentes localisations tumorales dans le rectum.

Volume–cible anatomoclinique dans la radiothérapie préopératoire des cancers du rectum

Resume L’exerese totale du mesorectum permet d’augmenter nettement le taux de controle local des cancers rectaux, ce qui signifie que le mesorectum est l’espace anatomique principal au sein duquel les recidives locales vont se developper. Il devient donc l’element de base de la reflexion de l’oncologue radiotherapeute dans l’elaboration du volume–cible anatomoclinique dans le cadre d’une irradiation preoperatoire. Nous proposons de l’identifier sur les structures anatomiques d’une scanographie effectuee en position de traitement.

Mise au pointCancers du rectum : volumes cible de la radiothérapie, bases rationnellesRectal cancer: The radiation basis of radiotherapy, target volume

Since the implementation of preoperative chemoradiotherapy and mesorectal excision, the 5-year rates of locoregional failures in T3-T4 N0-N1 M0 rectal cancer fell from 25-30% thirty years ago to 5-8% nowadays. A critical analysis of the locoregional failures sites and mechanisms, as well as the identification of nodal extension, helps the radiation oncologist to optimize the radiotherapy target definition. The upper limit of the clinical target volume is usually set at the top of the third sacral vertebra. The lateral pelvic nodes should be included when the tumor is located in the distal part of the rectum. The anal sphincter and the levator muscles should be spared when a conservative surgery is planned. In case of abdominoperineal excision, the ischiorectal fossa and the sphincters should be included in the clinical target volume. A confrontation with radiologist and surgeon is mandatory to improve the definition of the target volumes to be treated.